Method and apparatus for controlling autonomic balance using neural stimulation

ABSTRACT

A neural stimulation system senses autonomic activities and applies neural stimulation to sympathetic and parasympathetic nerves to control autonomic balance. The neural stimulation system is capable of delivering neural stimulation pulses for sympathetic excitation, sympathetic inhibition, parasympathetic excitation, and parasympathetic inhibition.

TECHNICAL FIELD

This document generally relates to medical devices and particularly to aneural stimulation system that controls autonomic balance.

BACKGROUND

The heart is the center of a person's circulatory system. The leftportions of the heart draw oxygenated blood from the lungs and pump itto the organs of the body to provide the organs with their metabolicneeds for oxygen. The right portions of the heart draw deoxygenatedblood from the body organs and pump it to the lungs where the blood getsoxygenated. These pumping functions are accomplished by cycliccontractions of the myocardium (heart muscles). In a normal heart, thesinoatrial node generates electrical impulses called action potentials.The electrical impulses propagate through an electrical conductionsystem to various regions of the heart to excite the myocardial tissueof these regions. Coordinated delays in the propagations of the actionpotentials in a normal electrical conduction system cause the variousportions of the heart to contract in synchrony to result in efficientpumping functions indicated by a normal hemodynamic performance. Ablocked or otherwise abnormal electrical conduction system and/ordeteriorated myocardial tissue result in an impaired hemodynamicperformance, including a diminished blood supply to the heart and therest of the body.

The hemodynamic performance is modulated by neural signals in portionsof the autonomic nervous system. For example, the myocardium isinnervated with sympathetic and parasympathetic nerves. Neuralactivities on these nerves are known to regulate, among other things,heart rate, blood pressure, and myocardial contractility. Autonomicdysfunction is associated with cardiac dysfunctions and poor hemodynamicperformance. For example, in heart failure patients, reduced autonomicbalance (increase in sympathetic tone and decrease in parasympathetictone) is known to be associated with left ventricular dysfunction andincreased mortality. Examples of other conditions of autonomicdysfunction, collectively termed as dysautonomia, include posturalorthostatic tachycardia syndrome (POTS), neurocardiogenic syncope (NCS),pure autonomic failure (PAF), and multiple system atrophy (MSA).Patients having autonomic dysfunction and the associated cardiacdysfunctions can potentially benefit from controlling the autonomicbalance. For example, increasing parasympathetic tone and decreasingsympathetic tone may protect the myocardium by controlling adverseremodeling and preventing arrhythmias after myocardial infarction.Patients with bradycardia-tachycardia syndrome, a variant of sick sinussyndrome characterized by alternating periods of slow and rapid heartrate, may also benefit from regulation of autonomic function. For theseand other reasons, there is a need for a means to treat autonomicdysfunction or cardiac dysfunction by controlling autonomic balance.

SUMMARY

A neural stimulation system senses autonomic activities and appliesneural stimulation to sympathetic and parasympathetic nerves to controlautonomic balance. The neural stimulation system is capable ofdelivering neural stimulation pulses for sympathetic excitation,sympathetic inhibition, parasympathetic excitation, and parasympatheticinhibition.

In one embodiment, a neural stimulation system includes a stimulationoutput circuit, an autonomic balance monitoring circuit, and astimulation control circuit. The stimulation output circuit deliverssympathetic stimulation pulses and parasympathetic stimulation pulses.The autonomic balance monitoring circuit senses one or more signalsindicative of autonomic activities. The stimulation control circuitincludes a sympathetic stimulation controller and a parasympatheticstimulation controller. The sympathetic stimulation controller controlsthe delivery of the sympathetic stimulation pulses for sympatheticexcitation and sympathetic inhibition. The parasympathetic stimulationcontroller controls the delivery of the parasympathetic stimulationpulses for parasympathetic excitation and parasympathetic inhibition.

In one embodiment, a method for neural stimulation provides forsympathetic excitation, sympathetic inhibition, parasympatheticexcitation, and/or parasympathetic inhibition. One or more signalsindicative of autonomic activities are sensed. Delivery of sympatheticand parasympathetic stimulation pulses is controlled using feedbackcontrol, with one or more inputs including the one or more signalsindicative of autonomic activities. This includes controlling thedelivery of the sympathetic stimulation pulses for sympatheticexcitation and sympathetic inhibition and controlling the delivery ofthe parasympathetic stimulation pulses for parasympathetic excitationand parasympathetic inhibition.

This Summary is an overview of some of the teachings of the presentapplication and not intended to be an exclusive or exhaustive treatmentof the present subject matter. Further details about the present subjectmatter are found in the detailed description and appended claims. Otheraspects of the invention will be apparent to persons skilled in the artupon reading and understanding the following detailed description andviewing the drawings that form a part thereof. The scope of the presentinvention is defined by the appended claims and their legal equivalents.

BRIEF DESCRIPTION OF THE DRAWINGS

In the drawings, which are not necessarily drawn to scale, like numeralsdescribe similar components throughout the several views. The drawingsillustrate generally, by way of example, various embodiments discussedin the present document.

FIG. 1 is an illustration of an embodiment of a neural stimulationsystem for controlling autonomic balance and portions of an environmentin which the neural stimulation system is used.

FIG. 2 is an illustration of an embodiment of a method for controllingautonomic balance by neural stimulation.

FIG. 3 is a block diagram illustrating an embodiment of a neuralstimulation circuit of the neural stimulation system.

FIG. 4 is a block diagram illustrating an embodiment of a stimulationcontrol circuit of the neural stimulation circuit.

FIG. 5 is a block diagram illustrating an embodiment of an autonomicbalance monitoring circuit of the neural stimulation circuit.

FIG. 6 is a block diagram illustrating an embodiment of a nerve trafficsensing circuit of the autonomic balance monitoring circuit.

FIG. 7 is a block diagram illustrating an embodiment of a surrogatesignal sensing circuit of the autonomic balance monitoring circuit.

FIG. 8 is a block diagram illustrating an embodiment of a physiologicalfunction sensing circuit of the autonomic balance monitoring circuit.

FIG. 9 is a block diagram illustrating an embodiment of an implantablemedical device including the neural stimulation circuit and a cardiacstimulation circuit.

FIG. 10 is a block diagram illustrating an embodiment of an externalsystem communicating with the implantable medical device.

FIGS. 11A and 11B are illustrations of neural mechanisms for peripheralvascular control.

FIGS. 12A-C are illustrations of a heart.

FIG. 13 is an illustration of baroreceptors and afferent nerves in thearea of the carotid sinuses and aortic arch.

FIG. 14 is an illustration of baroreceptors in and around the pulmonaryartery.

FIG. 15 is an illustration of baroreceptor fields in the aortic arch,the ligamentum arteriosum and the trunk of the pulmonary artery.

FIG. 16 is an illustration of an example of a neural response afterperturbing a physiological system.

FIG. 17 is a flow chart illustrating an embodiment of a method of neuralstimulation for controlling autonomic balance.

DETAILED DESCRIPTION

In the following detailed description, reference is made to theaccompanying drawings which form a part hereof, and in which is shown byway of illustration specific embodiments in which the invention may bepracticed. These embodiments are described in sufficient detail toenable those skilled in the art to practice the invention, and it is tobe understood that the embodiments may be combined, or that otherembodiments may be utilized and that structural, logical and electricalchanges may be made without departing from the scope of the presentinvention. References to “an”, “one”, or “various” embodiments in thisdisclosure are not necessarily to the same embodiment, and suchreferences contemplate more than one embodiment. The following detaileddescription provides examples, and the scope of the present invention isdefined by the appended claims and their legal equivalents.

This document discusses a neural stimulation system that senses andcontrols autonomic balance. Implantable neural leads include electrodesfor placement in or about sympathetic and parasympathetic nerves tosense neural activities from and deliver neural stimulation pulses tothese nerves. The neural stimulation pulses include electrical pulsesthat stimulate one or more nerves. An implantable neural stimulationdevice delivers the neural stimulation pulses to the sympathetic andparasympathetic nerves to control autonomic balance by using a selectivecombination of sympathetic excitation (excitatory stimulation of thesympathetic nervous system), sympathetic inhibition (inhibitorystimulation of the sympathetic nervous system), parasympatheticexcitation (excitatory stimulation of the parasympathetic nervoussystem), and parasympathetic inhibition (inhibitory stimulation of theparasympathetic nervous system). Such a device is capable of deliveringa therapy with a broad range of therapeutic effects and/or overallstimulation intensity. For example, delivering the sympatheticinhibition and the parasympathetic excitation simultaneously has thepotential of providing for a substantially stronger effect and/oradditional therapeutic effects when compared to delivering either thesympathetic inhibition or the parasympathetic excitation alone.Simultaneous delivery of excitatory and inhibitory stimulation to one ofthe sympathetic and parasympathetic nervous system provides for abroader range of control of systemic as well as localized physiologicalfunctions. For example, delivering excitatory and inhibitory stimulationsimultaneously to two efferent nerves of the sympathetic orparasympathetic nervous system may allow individualized control of twoorgans or two portions of an organ each innervated by one of theseefferent nerves. Simultaneous delivery of excitatory stimulation to anafferent nerve and inhibitory stimulation to an efferent nerve, orinhibitory stimulation to an afferent nerve and excitatory stimulationto an efferent nerve, of the same nervous system allows simultaneousgeneral control of systemic activities (e.g., central nervous systemactivities) and specific control of local activities (e.g., peripheralorgan activities).

FIG. 1 is an illustration of an embodiment of a neural stimulationsystem 100 for controlling autonomic balance and portions of anenvironment in which system 100 is used. System 100 includes implantablemedical device 110 that delivers neural stimulation pulses through leads106 and 108, an external system 120, and a telemetry link 125 providingfor communication between implantable medical device 110 and externalsystem 120.

System 100 controls autonomic balance by delivering neural stimulationpulses to sympathetic and parasympathetic nerves. For illustrativepurpose only, FIG. 1 shows that lead 106 includes an electrode 107coupled to a nerve 102 of the sympathetic nervous system, and lead 108includes an electrode 109 coupled to a nerve 104 of the parasympatheticnervous system. Nerves 102 and 104 innervate a heart 101. In variousembodiments, implantable medical device 110 provides neural stimulationto any one or more nerves through one or more implantable neural leadsto control autonomic balance. Such implantable neural leads each includeat least one electrode for sensing neural activities and deliveringneural stimulation pulses. Examples of such implantable neural leadsinclude an expandable stimulation lead having an electrode for placementin a pulmonary artery in a proximity of a high concentration ofbaroreceptors, a transvascular lead having an electrode for placementproximal to a cardiac fat pad, an epicardial lead having an electrodefor placement in a cardiac fat pad, a lead having a cuff electrode forplacement around an aortic, carotid, or vagus nerve, an intravascularlyfed lead having an electrode for placement proximal to the aortic,carotid, or vagus nerve for transvascularly delivering the neuralstimulation pulses to that nerve, and a lead having an electrode forplacement in a spinal cord, on the spinal cord dorsal or ventral nerves,or in the sympathetic ganglia or nerves.

Implantable medical device 110 includes a neural stimulation circuit130. Neural stimulation circuit 130 delivers sympathetic stimulationpulses (electrical pulses that stimulate one or more sympathetic nerves)and parasympathetic stimulation pulses (electrical pulses that stimulateone or more parasympathetic nerves). The delivery of the sympatheticstimulation pulses and the delivery of the parasympathetic stimulationpulses are individually controllable and coordinated. By controllingstimulation parameters, the sympathetic stimulation pulses are deliveredto increase or decrease the sympathetic tone, and the parasympatheticstimulation pulses are delivered to increase or decrease theparasympathetic tone. In various embodiments, implantable medical device110 is capable of sensing physiological signals and/or deliveringtherapies in addition to the neural stimulation. Examples of suchadditional therapies include cardiac pacing therapy,cardioversion/defibrillation therapy, cardiac resynchronization therapy(CRT), cardiac remodeling control therapy (RCT), drug therapy, celltherapy, and gene therapy. In various embodiments, implantable medicaldevice 110 delivers the neural stimulation in coordination with one ormore such additional therapies.

External system 120 communicates with implantable medical device 110 andprovides for access to implantable medical device 110 by a physician orother caregiver. In one embodiment, external system 120 includes aprogrammer. In another embodiment, external system 120 is a patientmanagement system including an external device communicating withimplantable medical device 110 via telemetry link 125, a remote devicein a relatively distant location, and a telecommunication networklinking the external device and the remote device. The patientmanagement system allows access to implantable medical device 110 from aremote location, for purposes such as monitoring patient status andadjusting therapies. In one embodiment, telemetry link 125 is aninductive telemetry link. In an alternative embodiment, telemetry link125 is a far-field radio-frequency (RF) telemetry link. Telemetry link125 provides for data transmission from implantable medical device 110to external system 120. This includes, for example, transmittingreal-time physiological data acquired by implantable medical device 110,extracting physiological data acquired by and stored in implantablemedical device 110, extracting patient history data such as occurrencesof arrhythmias and therapy deliveries recorded in implantable medicaldevice 110, and/or extracting data indicating an operational status ofimplantable medical device 110 (e.g., battery status and leadimpedance). Telemetry link 125 also provides for data transmission fromexternal system 120 to implantable medical device 110. This includes,for example, programming implantable medical device 110 to acquirephysiological data, programming implantable medical device 110 toperform at least one self-diagnostic test (such as for a deviceoperational status), and/or programming implantable medical device 110to deliver one or more therapies and/or to adjust the delivery of one ormore therapies.

FIG. 2 is an illustration of an embodiment of a method for controllingautonomic balance by neural stimulation. A balance beam representsautonomic balance, which is shown in FIG. 2 as being in a balancedposition. A counterclockwise rotation of the balance beam indicates thatthe autonomic balance shifts to the sympathetic nervous system, with arelative high sympathetic tone and a relatively low parasympathetictone. A clockwise rotation of the balance beam indicates that theautonomic balance shifts to the parasympathetic nervous system, with arelative low sympathetic tone and a relatively high parasympathetictone. As illustrated in FIG. 2, the balance of the beam, i.e., theautonomic balance, is controlled by applying one or more of sympatheticexcitation, sympathetic inhibition, parasympathetic excitation, andparasympathetic inhibition. By controlling stimulation parameters, thesympathetic stimulation pulses are delivered for either sympatheticexcitation, which increases the sympathetic tone, or sympatheticinhibition, which decreases the sympathetic tone. The parasympatheticstimulation pulses are delivered for either parasympathetic excitation,which increases the parasympathetic tone, or parasympathetic inhibition,which decreases the parasympathetic tone. A combination of thesympathetic excitation, sympathetic inhibition, parasympatheticexcitation, and parasympathetic inhibition brings the balance beam tothe balanced position or a desirable shifted position.

FIG. 3 is a block diagram illustrating an embodiment of a neuralstimulation circuit 330, which is a specific embodiment of neuralstimulation circuit 130. Neural stimulation circuit 330 includes astimulation output circuit 332, an autonomic balance monitoring circuit334, and a stimulation control circuit 336. Stimulation output circuit332 delivers sympathetic stimulation pulses and parasympatheticstimulation pulses through one or more neural leads such as thosediscussed in this document. Autonomic balance monitoring circuit 334senses one or more signals indicative of autonomic activities such asnerve traffic in one or more nerves of the autonomic nervous system orphysiological activities affected by the autonomic activities. Invarious embodiments, the one or more signals indicative of autonomicactivities include one or more signals indicative of the autonomicstate. Stimulation control circuit 336 controls the delivery of neuralstimulation pulses based on the one or more signals indicative ofautonomic activities. Stimulation control circuit 336 includes asympathetic stimulation controller 338 and a parasympathetic stimulationcontroller 340. Sympathetic stimulation controller 338 controls thedelivery of the sympathetic stimulation pulses for the sympatheticexcitation and the sympathetic inhibition. Parasympathetic stimulationcontroller 340 controls the delivery of the parasympathetic stimulationpulses for the parasympathetic excitation and the parasympatheticinhibition. Sympathetic stimulation controller 338 and parasympatheticstimulation controller 340 allow the delivery of the sympatheticstimulation pulses and the delivery of the parasympathetic stimulationpulses to be individually controllable. In one embodiment, stimulationoutput circuit 332, autonomic balance monitoring circuit 334, andstimulation control circuit 336 are housed in a hermetically sealedimplantable housing to form an implantable medical device.

FIG. 4 is a block diagram illustrating an embodiment of a stimulationcontrol circuit 436, which is a specific embodiment of stimulationcontrol circuit 336. Stimulation control circuit 436 controls thedelivery of the sympathetic stimulation pulses and parasympatheticstimulation pulses based on the one or more signals indicative ofautonomic activities sensed by autonomic balance monitoring circuit 334and the programmed goals of autonomic balance monitoring circuit 334.Stimulation control circuit 436 includes a pulse delivery controlcircuit 442 and a stimulation parameter adjustment circuit 444.

Pulse delivery control circuit 442 controls the delivery of thesympathetic stimulation pulses and the parasympathetic stimulationpulses using a plurality of stimulation parameters received fromstimulation parameter adjustment circuit 444. Pulse delivery controlcircuit 442 includes a sympathetic stimulation controller 438 and aparasympathetic stimulation controller 440. Sympathetic stimulationcontroller 438 controls the delivery of the sympathetic stimulationpulses for the sympathetic excitation and the sympathetic inhibition.Parasympathetic stimulation controller 440 controls the delivery of theparasympathetic stimulation pulses for parasympathetic excitation andparasympathetic inhibition. In one embodiment, the stimulation frequencydetermines whether the electrical stimulation pulses delivered to anerve results in the excitation or inhibition of that nerve. Thestimulation frequency is controlled by a stimulation parameterspecifying the frequency at which the electrical stimulation pulses aredelivered (in number of pulses per second, for example). Alternatively,the stimulation frequency is controlled by a stimulation parameterspecifying the interval between two consecutive electrical stimulationpulses (in milliseconds, for example). When the stimulation frequency isbelow a certain level, the electrical stimulation pulses delivered to anerve excites that nerve, resulting in increased nerve traffic. When thestimulation frequency is above another certain level, the electricalstimulation pulses delivered to a nerve inhibits that nerve, resultingin decreased nerve traffic. In another embodiment, the stimulationpolarity determines whether the electrical stimulation pulses deliveredto a nerve results in the excitation or inhibition of that nerve. Axonaction potentials are excited by a current depolarizing an axon andblocked by a current hyperpolarizing the axon. Thus, stimulation withcathodal current excites a nerve by exciting axon action potentials, andstimulation with anodal current inhibits the nerve by blocking axonaction potentials. In a specific embodiment, the stimulation polarity iscontrolled by using bipolar electrode configuration on a nerve andcontrolling the direction of stimulation current flow between twoelectrodes. In a further embodiment, the stimulation polarity andintensity determine the direction of nerve traffic as a result of neuralstimulation. When electrical stimulation pulses are delivered to a nerveusing two electrodes in a bipolar configuration, the evoked axon actionpotentials propagate in both afferent and efferent directions of theaxon when the stimulation intensity is within a certain range. When thestimulation intensity is above a certain level, “anodal block” occurs.The action potential is blocked in the direction from the cathode to theanode while stilling propagating in the direction from the anode to thecathode. This allows, for example, selection of excitatory stimulationor inhibitory stimulation of a nerve innervating an organ by controllingthe stimulation polarity and intensity. The excitatory (efferent)stimulation is selected by designating the electrode closer to thecentral nervous system as the anode and setting the stimulationintensity to a level at which the anodal block occurs. The inhibitory(afferent) stimulation is selected by designating the electrode closerto the organ as the anode and setting the stimulation intensity to alevel at which the anodal block occurs. The stimulation has theinhibitory effect because of the negative feedback reflex circuits.

Stimulation parameter adjustment circuit 444 adjusts the plurality ofstimulation parameters used by pulse delivery control circuit 442 basedon the one or more signals indicative of autonomic activities and thetherapeutic objectives. The therapeutic objectives are programmed bymapping the autonomic state (input) to the stimulation parameters(output) using feedback control to shift the sensed autonomic state to adesired autonomic state. In one embodiment, stimulation parameteradjustment circuit 444 adjusts the plurality of stimulation parametersdynamically using feedback control with one or more inputs including theone or more signals indicative of autonomic activities. Examples of suchsignals indicative of autonomic activities include neural signals,surrogate signals, and physiological function signals. In oneembodiment, stimulation parameter adjustment circuit 444 adjusts theplurality of stimulation parameters based on one or more neural signals.Neural activities indicated by the one or more neural signals providefor a direct measure of the autonomic state. In another embodiment,stimulation parameter adjustment circuit 444 adjusts the plurality ofstimulation parameters based on one or more surrogate signals. Asurrogate signal is a signal sensed as a measure or indication of theautonomic balance. In another embodiment, stimulation parameteradjustment circuit 444 adjusts the plurality of stimulation parametersbased on one or more physiological function signals. Such physiologicalfunction signals are each a measure or an indication of effects of theautonomic balance. In various other embodiments, stimulation parameteradjustment circuit 444 adjusts the plurality of stimulation parametersbased on a combination of two or more of the neural signal(s), thesurrogate signal(s), and the physiological function signal(s). Thisallows adjustment of the stimulation parameters based on both theautonomic activities and their effects in selected physiologicalfunctions. In one embodiment, stimulation parameter adjustment circuit444 adjusts the plurality of stimulation parameters based on the one ormore neural signals and the one or more physiological function signals.In another embodiment, stimulation parameter adjustment circuit 444adjusts the plurality of stimulation parameters based on the one or moresurrogate signals and the one or more physiological function signals.The neural, surrogate, and physiological signals and their sensing arefurther discussed below, with reference to FIGS. 5-8.

In one embodiment, the plurality of stimulation parameters includes oneor more sympathetic stimulation parameters and one or moreparasympathetic stimulation parameters. The one or more sympatheticstimulation parameters control the delivery of the sympatheticstimulation pulses for the sympathetic excitation and the sympatheticinhibition. The one or more parasympathetic stimulation parameterscontrol the delivery of the parasympathetic stimulation pulses for theparasympathetic excitation and the parasympathetic inhibition. In thisembodiment, as illustrated in FIG. 4, stimulation parameter adjustmentcircuit 444 includes a sympathetic stimulation parameter adjustmentmodule 446 and a parasympathetic stimulation parameter adjustment module448. Sympathetic stimulation parameter adjustment module 446 adjusts theone or more sympathetic stimulation parameters. Parasympatheticstimulation parameter adjustment module 448 adjusts the one or moreparasympathetic stimulation parameters.

In one embodiment, stimulation parameter adjustment circuit 444 adjuststhe plurality of stimulation parameters based on a predetermined timeschedule, in addition to the one or more signals indicative of autonomicactivities. For example, a heart failure patient suffers from poorhemodynamic performance and adverse myocardial remodeling. To improvethe hemodynamic performance, the autonomic balance is shifted toincrease the sympathetic tone and/or decrease the parasympathetic tone.To control the myocardial remodeling, the autonomic balance is shiftedto decrease the sympathetic tone and/or increase the parasympathetictone. One example of a treatment strategy is to adjust the stimulationparameters based on a time schedule made according to the patient'santicipated daily activities. For example, the stimulation parametersare adjusted for increasing the sympathetic tone and/or decreasing theparasympathetic tone during the day and for decreasing the sympathetictone and/or increasing the parasympathetic tone at night. In anotherembodiment, stimulation parameter adjustment circuit 444 adjusts theplurality of stimulation parameters based on a signal indicative of aneed to shift the autonomic balance, in addition to the one or moresignals indicative of autonomic activities. For example, for the sameheart failure patient, an activity level signal is used to indicate thepatient's gross physical activity level, which in turn indicates a needto increase hemodynamic performance. The activity level signal is sensedusing an activity sensor such as an implantable accelerometer orpiezoelectric crystal. When the activity level signal exceeds apredetermined threshold, the stimulation parameters are adjusted forincreasing the sympathetic tone and/or decreasing the parasympathetictone. This improves the patient's hemodynamic performance to meet themetabolic demand for the patient's activity, but may have undesirableeffects in the myocardial remodeling. When the activity level signalfalls below another predetermined threshold, the stimulation parametersare adjusted for decreasing the sympathetic tone and/or increasing theparasympathetic tone. This provides control of the myocardial remodelingwhen the metabolic demand is low. In another example, a patientsuffering from brady-tachy syndrome has a cardiac rhythm oscillatingbetween bradycardia and tachycardia. To treat the patient by regulatingthe heart rate, the autonomic balance is shifted when the heart ratefalls into a bradycardia rate window or a tachycardia rate window. Whenthe heart rate falls below a predetermined threshold, the stimulationparameters are adjusted for increasing the sympathetic tone and/ordecreasing the parasympathetic tone, thereby increasing the patient'sheart rate. When the heart rate exceeds a predetermined threshold, thestimulation parameters are adjusted for decreasing the sympathetic toneand/or increasing the parasympathetic tone, thereby decreasing thepatient's heart rate.

In one embodiment, stimulation parameter adjustment circuit 444 isprogrammable via telemetry to adjust the plurality of stimulationparameters used by pulse delivery control circuit 442 according totherapeutic objectives set by a physician or other caregiver. Themapping between the one or more signals indicative of autonomicactivities and the stimulation parameters is programmable withprogrammable parameters specifying the responsiveness of the feedbackcontrol. Such parameters affect, for example, how quickly thestimulation parameters are adjusted in response to a sensed change inthe autonomic state, the sensitivity of the feedback control, the limitswithin which the autonomic state is to be adjusted or maintained, andthe limits of the output level (e.g., stimulation intensity).

FIG. 5 is a block diagram illustrating an embodiment of an autonomicbalance monitoring circuit 534, which is a specific embodiment ofautonomic balance monitoring circuit 334. Autonomic balance monitoringcircuit 534 provides stimulation control circuit 336 (or 436) with theone or more signals indicative of autonomic activities.

In one embodiment, as illustrated in FIG. 5, autonomic balancemonitoring circuit 534 includes a nerve traffic sensing circuit 550, asurrogate signal sensing circuit 552, and a physiological functionsensing circuit 554. In various embodiments, depending on which of theone or more signals indicative of autonomic activities are used bystimulation control circuit 336 (or 436), autonomic balance monitoringcircuit 534 includes any one, a combination of any two, or a combinationof all three of nerve traffic sensing circuit 550, surrogate signalsensing circuit 552, and physiological function sensing circuit 554.

FIG. 6 is a block diagram illustrating an embodiment of a nerve trafficsensing circuit 650, which is a specific embodiment of nerve trafficsensing circuit 550. Nerve traffic sensing circuit 650 senses one ormore neural signals that directly indicate the autonomic state. Nervetraffic sensing circuit 650 includes a sympathetic traffic sensingcircuit 656 and a parasympathetic traffic sensing circuit 658.Sympathetic traffic sensing circuit 656 sense at least one sympatheticneural signal indicative of sympathetic nerve traffic. Parasympathetictraffic sensing circuit 658 senses at least one parasympathetic neuralsignal indicative of parasympathetic nerve traffic.

FIG. 7 is a block diagram illustrating an embodiment of a surrogatesignal sensing circuit 752, which is a specific embodiment of surrogatesignal sensing circuit 552. Surrogate signal sensing circuit 752 sensesone or more surrogate signals each indicative of autonomic activitiesand used as a measure of the autonomic state. Surrogate signal sensingcircuit 752 includes a heart rate variability (HRV) sensing circuit 760to sense HRV and produce an HRV signal. HRV is the beat-to-beat variancein cardiac cycle length over a period of time. The HRV signal is asignal representative of an HRV parameter that includes any parameterbeing a measure of the HRV, including any qualitative expression of thebeat-to-beat variance in cardiac cycle length over a period of time. TheHRV parameter includes any parameter being a measure of the HRV,including any qualitative expression of the beat-to-beat variance incardiac cycle length over a period of time. In a specific embodiment,the HRV parameter includes the ratio of Low-Frequency (LF) HRV toHigh-Frequency (HF) HRV (LF/HF ratio). The LF HRV includes components ofthe HRV having frequencies between about 0.04 Hz and 0.15 Hz. The HF HRVincludes components of the HRV having frequencies between about 0.15 Hzand 0.40 Hz. The LF/HF ratio is used to track trends in shifts ofautonomic balance. For example, a substantial change in the LF /HF ratioindicates a change in systemic stress that indicates the degree to whichthe sympathetic nervous system is over-stimulated.

FIG. 8 is a block diagram illustrating an embodiment of a physiologicalfunction sensing circuit 854, which is a specific embodiment ofphysiological function sensing circuit 554. Physiological functionsensing circuit 854 senses one or more physiological function signalseach affected by autonomic activities. Such a physiological functionsignal indicates a need to control the autonomic balance to result in adesirable change or restoration of a physiological function.Physiological function sensing circuit 854 includes one or more of aheart rate sensing circuit 862 to sense a heart rate and rhythm, anactivity sensing circuit 864 to sense a physical activity level, arespiration sensing circuit 866 to sense a respiratory signal indicativeof respiratory rate, rhythm tidal volume, and cardiac stroke volume, animpedance sensing circuit 868 to sense a signal indicative of strokevolume, such as a cardiac impedance or a transthoracic impedance, aheart sound sensing circuit 870 to sense a signal indicative of cardiacsystolic and diastolic timing, ventricular contractility, and fillingpressure, and a pressure sensing circuit 872 to sense a signalindicative of a blood pressure.

FIG. 9 is a block diagram illustrating an embodiment of an implantablemedical device 910 coupled to neural lead(s) 903 and cardiac lead(s)905. Implantable medical device 910, which is a specific embodiment ofimplantable medical device 110, is an integrated cardiac and neuralstimulation device and includes a neural stimulation circuit 930, acardiac stimulation circuit 980, and an implant telemetry circuit 974.Neural lead(s) 903 includes one or more implantable neural leads eachincluding at least one electrode configured for sensing neuralactivities and delivering neural stimulation pulses. Cardiac lead(s) 905includes one or more implantable cardiac stimulation leads eachincluding at least one endocardial or epicardial electrode configuredfor sensing cardiac activities and delivering cardiac stimulationpulses. Neural stimulation circuit 930 is a specific embodiment ofneural stimulation circuit 130 that communicates with cardiacstimulation circuit 980 for coordinated cardiac and neural stimulations.Examples of the cardiac stimulation circuit 980 include a pacingcircuit, a cardioversion/defibrillation circuit, a CRT device, and/or anRCT device. Cardiac stimulation circuit 980 also provides for sensing ofone or more cardiac signals including electrograms. In one embodiment,cardiac stimulation circuit 980 provides the one or more signalsindicative of autonomic activities. In various embodiments, implantablemedical device 910 further includes one or more of a drug deliverydevice, a biological therapy device, and any other device thatsupplements the functions of neural stimulation circuit 930 and cardiacstimulation circuit 980. Implant telemetry circuit 974 communicates withexternal system 120 via telemetry link 125.

In one embodiment, one or more sensors 990 are coupled to implantablemedical devices 910 via one or more electrical connections and/ortelemetry links. Sensor(s) 990 are external to implantable medicaldevices 910 and perform, for example, one or more functions of heartrate sensing circuit 862, activity sensing circuit 864, respirationsensing circuit 866, impedance sensing circuit 868, heart sound sensingcircuit 870, and pressure sensing circuit 872. In general, variousspecific embodiments of system 100 use physiological sensors that areexternal to implantable medical device 110 and communicate withimplantable medical device 110 via electrical connections and/ortelemetry links. Such physiological sensors include implantable sensors,external sensors, or both.

FIG. 10 is a block diagram illustrating an embodiment of an externalsystem 1020, which is a specific embodiment of external system 120. Asillustrated in FIG. 10, external system 1020 is a patient managementsystem including an external device 982, a telecommunication network984, and a remote device 986. External device 982 is placed within thevicinity of implantable medical device 110 or 910 and includes externaltelemetry system 988 to communicate with the implantable medical devicevia telemetry link 125. Remote device 986 is in a remote location andcommunicates with external device 982 through network 984, thus allowinga physician or other caregiver to monitor and treat a patient from adistant location and/or allowing access to various treatment resourcesfrom the remote location.

According to the present subject matter, neural stimulation pulses aredelivered to the sympathetic nervous system and the parasympatheticnervous system through one or more neural leads. In various embodiments,neural signals are sensed from the sympathetic nervous system and theparasympathetic nervous system through the one or more neural leads.Examples of sites to which the neural stimulation pulses are deliveredand from which neural signals are sense include a site in a pulmonaryartery in a proximity of a high concentration of baroreceptors, acardiac fat pad, an aortic nerve, a carotid nerve, a vagus nerve, avascular site proximal to the aortic, carotid, or vagus nerve, and sitesin the spinal cord, on the spinal cord dorsal or ventral nerves, or inthe sympathetic ganglia or nerves. Electrodes of the one or more neuralleads are placed in one or more such sites for neural sensing andstimulation.

A brief discussion of the physiology related to baroreceptors andchemoreceptors is provided below. This brief discussion introduces theautonomic nervous system, baroreflex, and chemoreceptors to provide anunderstanding of placement of the electrodes (also referred to as neuraltraffic sensors) of the neural leads.

The autonomic nervous system (ANS) regulates “involuntary” organs, whilethe contraction of voluntary (skeletal) muscles is controlled by somaticmotor nerves. Examples of involuntary organs include respiratory anddigestive organs, and also include blood vessels and the heart. Often,the ANS functions in an involuntary, reflexive manner to regulateglands, to regulate muscles in the skin, eye, stomach, intestines andbladder, and to regulate cardiac muscle and the muscle around bloodvessels, for example.

The ANS includes, but is not limited to, the sympathetic nervous systemand the parasympathetic nervous system. The sympathetic nervous systemis affiliated with stress and the “fight or flight response” toemergencies. Among other effects, the “fight or flight response”increases blood pressure and heart rate to increase skeletal muscleblood flow, and decreases digestion to provide the energy for “fightingor fleeing.” The parasympathetic nervous system is affiliated withrelaxation and the “rest and digest response” which, among othereffects, decreases blood pressure and heart rate, and increasesdigestion to conserve energy. The ANS maintains normal internal functionand works with the somatic nervous system.

In various embodiments, neural stimulation is applied to affect theheart rate, blood pressure, vasodilation, and vasoconstriction. Theheart rate and contractile strength is increased when excitatorystimulation is applied to the sympathetic nervous system and wheninhibitory stimulation is applied the parasympathetic nervous system,and is decreased when inhibitory stimulation is applied the sympatheticnervous system or when excitatory stimulation is applied theparasympathetic nervous system. In various embodiments, nerve traffic isalso sensed to provide a surrogate parameter for another physiologicalparameter, such as heart rate, blood pressure and the like. FIGS. 11Aand 11B illustrate neural mechanisms for peripheral vascular control.FIG. 11A generally illustrates afferent nerves to vasomotor centers. Anafferent nerve conveys impulses toward a nerve center. A vasomotorcenter relates to nerves that dilate and constrict blood vessels tocontrol the size of the blood vessels. FIG. 11B generally illustratesefferent nerves from vasomotor centers. An efferent nerve conveysimpulses away from a nerve center.

Stimulation of the sympathetic and parasympathetic nervous systems isknown to have effects other than heart rate, contractile strength, andblood pressure. For example, excitatory stimulation of the sympatheticnervous system dilates the pupil, reduces saliva and mucus production,relaxes the bronchial muscle, reduces the successive waves ofinvoluntary contraction (peristalsis) of the stomach and the motility ofthe stomach, increases the conversion of glycogen to glucose by theliver, decreases urine secretion by the kidneys, and relaxes the walland closes the sphincter of the bladder. Excitatory stimulation of theparasympathetic nervous system and/or inhibitory stimulation of thesympathetic nervous system constrict the pupil, increases saliva andmucus production, contracts the bronchial muscle, increases secretionsand motility in the stomach and large intestine, and increases digestionin the small intestine, increases urine secretion, and contracts thewall and relaxes the sphincter of the bladder. The functions associatedwith the sympathetic and parasympathetic nervous systems are many andcan be complexly integrated with each other. Thus, an indiscriminatestimulation of the sympathetic and/or parasympathetic nervous systems toachieve a desired response, such as vasodilation, in one physiologicalsystem may also result in an undesired response in other physiologicalsystems. Additionally, sensing of nerve traffic for use as a surrogateparameter of a physiological parameter can depend on a number ofphysiological parameters. Various embodiments of the present subjectmatter perturb the physiological system with precisely located neuralstimulation, and monitor the nerve traffic response to the stimulation.

A pressoreceptive region or field is capable of sensing changes inpressure, such as changes in blood pressure. Pressoreceptor regions arereferred to herein as baroreceptors, which generally include any sensorsof pressure changes. For example, baroreceptors include afferent nervesand further include sensory nerve endings that provide baroreceptorfields that are sensitive to the stretching of the wall that resultsfrom increased blood pressure from within, and function as the receptorof a central reflex mechanism that tends to reduce the pressure.Baroreflex functions as a negative feedback system, and relates to areflex mechanism triggered by stimulation of a baroreceptor. Increasedpressure stretches blood vessels, which in turn activates baroreceptorsin the vessel walls. Activation of baroreceptors naturally occursthrough internal pressure and stretching of the arterial wall, whichexcites the parasympathetic nervous system causing baroreflex inhibitionof sympathetic nerve activity (SNA) and a reduction in systemic arterialpressure. An increase in baroreceptor activity induces a reduction ofSNA, which reduces blood pressure by decreasing peripheral vascularresistance. Centrally mediated reflex pathways modulate cardiac rate,contractility and excitability. Baroreceptors and chemoreceptors in theheart, great vessels, and lungs, transmit neural signals reflective ofcardiac activity through vagal and afferent fibers to the centralnervous system. Thus, physiological parameters, such as systemicarterial pressure, can be determined based on nerve traffic. Suchpressure information, for example, provides useful feedback informationto guide therapy such as neural therapy or cardiac stimulation therapysuch as CRT.

Baroreflex is a reflex triggered by stimulation of a baroreceptor. Abaroreceptor includes any sensor of pressure changes, such as sensorynerve endings in the wall of the auricles of the heart, vena cava,aortic arch and carotid sinus, that is sensitive to stretching of thewall resulting from increased pressure from within, and that functionsas the receptor of the central reflex mechanism that tends to reducethat pressure. Afferent nerves can also be electrically stimulated toinduce a baroreflex, which inhibits the sympathetic nerve activity andstimulates parasympathetic nerve activity. Afferent nerve trunks, suchas the vagus, aortic and carotid nerves, leading from the sensory nerveendings also form part of a baroreflex pathway. Stimulating a baroreflexpathway and/or baroreceptors inhibits sympathetic nerve activity,stimulates the parasympathetic nervous system and reduces systemicarterial pressure by decreasing peripheral vascular resistance andcardiac contractility. Baroreceptors are naturally stimulated byinternal pressure and the stretching of vessel wall (e.g. arterialwall).

Some aspects of the present subject matter locally sense specific nerveendings in vessel walls rather than or in addition to afferent and/orefferent nerve trunks. For example, some embodiments sense baroreceptorsites or fields in the pulmonary artery. Some embodiments of the presentsubject matter involve sensing baroreceptor sites or nerve endings inthe aorta, the chambers of the heart, some embodiments of the presentsubject matter involve sensing efferent pathways such as the fat pads ofthe heart, and some embodiments of the present subject matter involvestimulating an afferent nerve trunk, such as the vagus, carotid andaortic nerves. Various embodiments involve combinations of sensing nerveending, sensing efferent nerve pathways and sensing afferent nervepathways. Some embodiments sense nerve trunks using a cuff electrode,and some embodiments sense nerve trunks using an intravascular leadpositioned in a blood vessel proximate to the nerve. Examples ofafferent nerve trunks include the vagus, aortic and carotid nerves.Examples of efferent nerve trunks include the cardiac branches of thevagus nerve. Stimulation of efferent nerves such as these cardiacbranches or the nerves in cardiac fat pads conveys nervous impulses toan effector, and thus do not use the baroreflex negative feedback of thecentral nervous system, which responds to nerve activity on afferentnerves with nerve activity on efferent nerves. Some embodiments senseneural traffic at any of the above-identified neural stimulation sites.

FIGS. 12A-12C illustrate a heart. As illustrated in FIG. 12A, the heart1201 includes a superior vena cava 1202, an aortic arch 1203, and apulmonary artery 1204. As is discussed in more detail below, pulmonaryartery 1204 includes baroreceptors. A lead is capable of beingintravascularly inserted through a peripheral vein and through thetricuspid valve into the right ventricle of the heart (not expresslyshown in the figure) similar to a cardiac pacing lead, and continue fromthe right ventricle through the pulmonary valve into the pulmonaryartery. A portion of the pulmonary artery and aorta are proximate toeach other. Various embodiments sense neural activity by thebaroreceptor in the aorta using a lead intravascularly positioned in thepulmonary artery. Some embodiments also stimulate baroreceptors in theaorta. Aspects of the present subject matter provide a relativelynoninvasive surgical technique to implant a neural traffic sensor, withor without a baroreceptor stimulator, intravascularly into the pulmonaryartery.

FIGS. 12B-12C illustrate the right side and left side of the heart,respectively, and further illustrate cardiac fat pads. FIG. 12Billustrates the right atrium 1267, right ventricle 1268, sinoatrial node1269, superior vena cava 1202, inferior vena cava 1270, aorta 1271,right pulmonary veins 1272, and right pulmonary artery 1273. FIG. 12Balso illustrates a cardiac fat pad 1274 between superior vena cava 1202and aorta 1271. Autonomic ganglia in cardiac fat pad 1274 are stimulatedand/or nerve traffic is sensed in some embodiments using an electrodescrewed or otherwise inserted into the fat pad, and are stimulatedand/or nerve traffic is sensed in some embodiments using anintravenously-fed lead proximately positioned to the fat pad in a vesselsuch as the right pulmonary artery or superior vena cava, for example.FIG. 12C illustrates the left atrium 1275, left ventricle 1276, rightatrium 1267, right ventricle 1268, superior vena cava 1202, inferiorvena cava 1270, aorta 1271, right pulmonary veins 1272, left pulmonaryvein 1277, right pulmonary artery 1273, and coronary sinus 1278. FIG.12C also illustrates a cardiac fat pad 1279 located proximate to theright cardiac veins and a cardiac fat pad 1280 located proximate toinferior vena cava 1270 and left atrium 1275. Autonomic ganglia incardiac fat pad 1279 are stimulated and/or nerve traffic is sensed insome embodiments using an electrode screwed or otherwise inserted intocardiac fat pad 1279, and are stimulated and/or nerve traffic is sensedin some embodiments using an intravenously-fed lead proximatelypositioned to the fat pad in a vessel such as right pulmonary artery1273 or right pulmonary vein 1272, for example. Autonomic ganglia incardiac fat pad 1280 are stimulated and/or nerve traffic is sensed insome embodiments using an electrode screwed or otherwise inserted intothe fat pad, and are stimulated and/or nerve traffic is sensed in someembodiments using an intravenously-fed lead proximately positioned tothe fat pad in a vessel such as inferior vena cava 1270 or coronarysinus 1278 or a lead in left atrium 1275, for example.

FIG. 13 illustrates baroreceptors in the area of the carotid sinus 1305,aortic arch 1303 and pulmonary artery 1304. The aortic arch 1303 andpulmonary artery 1304 were previously illustrated with respect to theheart in FIG. 12A. As illustrated in FIG. 13, the vagus nerve 1306extends and provides sensory nerve endings 1307 that function asbaroreceptors in the aortic arch 1303, in carotid sinus 1305 and in thecommon carotid artery 1310. The glossopharyngeal nerve 1308 providesnerve endings 1309 that function as baroreceptors in carotid sinus 1305.These nerve endings 1307 and 1309, for example, are sensitive tostretching of the wall resulting from increased pressure from within.Activation of these nerve endings reduces pressure. Although notillustrated in the figures, the fat pads and the atrial and ventricularchambers of the heart also include baroreceptors. Cuffs have been placedaround afferent nerve trunks, such as the vagal nerve, leading frombaroreceptors to vasomotor centers to stimulate the baroreflex. Invarious embodiments, afferent nerve trunks are stimulated, and/or nervetraffic from the afferent nerve trunks are sensed, using a cuff orintravascularly-fed lead positioned in a blood vessel proximate to theafferent nerves.

FIG. 14 illustrates baroreceptors in and around a pulmonary artery 1404.The superior vena cava 1402 and the aortic arch 1403 are alsoillustrated. As illustrated, pulmonary artery 1404 includes a number ofbaroreceptors 1411. Furthermore, a cluster of closely spacedbaroreceptors is situated near the attachment of the ligamentumarteriosum 1412. FIG. 14 also illustrates the right ventricle 1413 ofthe heart, and the pulmonary valve 1414 separating right ventricle 1413from pulmonary artery 1404. According to various embodiments of thepresent subject matter, a lead is inserted through a peripheral vein andthreaded through the tricuspid valve into the right ventricle, and fromright ventricle 1413 through pulmonary valve 1414 and into pulmonaryartery 1404 to stimulate baroreceptors and/or sense nerve traffic fromthe baroreceptors in and/or around the pulmonary artery. In variousembodiments, for example, the lead is positioned to stimulate thecluster of baroreceptors and/or sense nerve traffic near ligamentumarteriosum 1412.

FIG. 15 illustrates baroreceptor fields 1512 in the aortic arch 1503,near the ligamentum arteriosum and the trunk of the pulmonary artery1504. Some embodiments position the lead in the pulmonary artery tostimulate baroreceptor sites and/or sense nerve traffic in the aortaand/or cardiac fat pads, such as are illustrated in FIGS. 12B-12C.

FIG. 16 illustrates an example of a neural response after perturbing aphysiological system. In this example, pressure functions as anindicator for a physiological system. The pressure is experimentallyinduced, leading to a reflex inhibition of sympathetic activity. Thesystem is illustrated in a first low pressure condition 1615 and asecond high pressure condition 1616. Nerve activity, illustrated aswaveforms 1617 and 1618, changes between the two conditions. The changemay be rather transient in nature if the nervous system quickly adaptsfrom the first to the second condition, or may be more sustained if thenervous system does not quickly adapt to the change in conditions.Regardless, an analysis of a sensed nerve traffic signal can extract orotherwise determine features of the signal indicative of the response.In the illustrated example, waveform 1617 associated with an integratedsympathetic nerve activity changes (e.g. change in slope and period ofwaveform) from the first to the second conditions. Additionally,waveform 1618 associated with a mean sympathetic nerve activity changes(e.g. a first level of nerve activity to a second level of nerveactivity) from the first to the second conditions. The integratedsympathetic nerve activity and mean sympathetic nerve activity waveformsare provided as examples. Other ways of sensing changes in the neuraltraffic signals can be used.

Various embodiments of the present subject matter sense nerve trafficcorresponding to chemoreceptors. The carotid and aortic bodies provide aconcentration of cardiovascular chemoreceptors. The carotid body liesdeep to the bifurcation of the common carotid artery or somewhat betweenthe two branches. The carotid body is a small, flattened, ovalstructure, 2 to 5 mm in diameter, with a characteristic structurecomposed of epithelioid cells, which are in close relation to capillarysinusoids, and an abundance of nerve fibers. Surrounding the carotidbody is a delicate fibrous capsule. It is part of the visceral afferentsystem of the body, containing chemoreceptor endings that respond to lowlevels of oxygen in the blood or high levels of carbon dioxide andlowered pH of the blood. It is supplied by nerve fibers from both theglossopharyngeal and vagus nerves.

The aortic bodies (glomera aortica) are chemoreceptors similar to thecarotid bodies. Afferent fibers from the aortic bodies rin in the rightvagus and have cell bodies in the inferior ganglion. The supracardialbodies (aortic paraganglia) are also chemoreceptors with their afferentfibers in the left vagus and cell bodies in the inferior ganglion.

In various embodiments of the present subject matter, neural signals aresensed, and neural therapies are delivered, by an implantable systemincluding an implantable medical device such as an implantable neuralstimulation device or an integrated cardiac and neural stimulationdevice. Although implantable systems are illustrated and discussed,various aspects and embodiments of the present subject matter can beimplemented in external devices. For example, neural signals can besensed, and neural stimulation can be delivered, using implantableleads, external electrodes, percutaneous leads, or any combination ofthese.

FIG. 17 is a flow chart illustrating an embodiment of a method of neuralstimulation for controlling autonomic balance. In one embodiment, themethod is performed by system 100.

One or more signals indicative of autonomic activities are sensed at1710. Examples of such signals include neural signals, surrogatesignals, and physiological function signals. The neural signals directlyindicate the autonomic state. In one embodiment, the neural signalsinclude at least one sympathetic neural signal indicative of sympatheticnerve traffic and at least one parasympathetic neural signal indicativeof parasympathetic nerve traffic. The surrogate signals are each asignal known to indicate autonomic activities. In one embodiment, theLF/HF ratio is used as a surrogate signal being a surrogate of theautonomic state. The physiological function signals each indicate aphysiological function controlled or affected by the autonomicactivities. In one embodiment, the physiological function signalsinclude one or more of signals indicative of heart rate, activity level,respiratory activities, transthoracic impedance, heart sounds, and bloodpressures.

Delivery of sympathetic and parasympathetic stimulation pulses arecontrolled using feedback control at 1720. The one or more signalssensed at 1710 serve as input for the feedback control. As illustratedin FIG. 17, the feedback control is applied to control the delivery ofthe sympathetic stimulation pulses for sympathetic excitation andsympathetic inhibition at 1722 and to control the delivery of theparasympathetic stimulation pulses for parasympathetic excitation andparasympathetic inhibition at 1724. In one embodiment, the delivery ofsympathetic and parasympathetic stimulation pulses is controlled toachieve a desired autonomic balance. In one embodiment, the delivery ofsympathetic and parasympathetic stimulation pulses is controlled toshift autonomic balance for a predetermined period of time. Theautonomic balance is shifted in one direction by increasing sympathetictone and/or decreasing parasympathetic tone or in the other direction bydecreasing sympathetic tone and/or increasing parasympathetic tone. Inone embodiment, the delivery of sympathetic and parasympatheticstimulation pulses is controlled to control the autonomic balanceaccording to a predetermined schedule. For example, the autonomicbalance is shifted to result in a desirable performance of aphysiological function when the use of that function is anticipated forcertain times of day.

The delivery of the sympathetic and parasympathetic stimulation pulsesare controlled by adjusting a plurality of stimulation parameters basedon the one or more signals indicative of autonomic activities. Thisincludes adjusting one or more sympathetic stimulation parameterscontrolling the sympathetic excitation and the sympathetic inhibitionand one or more parasympathetic stimulation parameters controlling theparasympathetic excitation and the parasympathetic inhibition. In oneembodiment, the stimulation parameters are adjusted based on one or moreneural signals sensed at 1710. In another embodiment, the stimulationparameters are adjusted based on one or more surrogate signals sensed at1710. In another embodiment, the stimulation parameters are adjustedbased on one or more physiological function signals sensed at 1710. Inanother embodiment, the stimulation parameters are adjusted based on theone or more neural signals and the one or more physiological functionsignals. In another embodiment, the stimulation parameters are adjustedbased on the one or more surrogate signals and the one or morephysiological function signals.

It is to be understood that the above detailed description is intendedto be illustrative, and not restrictive. Other embodiments will beapparent to those of skill in the art upon reading and understanding theabove description. The scope of the invention should, therefore, bedetermined with reference to the appended claims, along with the fullscope of legal equivalents to which such claims are entitled.

1. A neural stimulation system for stimulating at least a sympatheticnerve and a parasympathetic nerve, the system comprising: a stimulationoutput circuit adapted to deliver stimulation pulses includingsympathetic stimulation pulses delivered to the sympathetic nerve at asympathetic stimulation frequency and parasympathetic stimulation pulsesdelivered to the parasympathetic nerve at a parasympathetic stimulationfrequency; an autonomic balance monitoring circuit adapted to sense oneor more signals indicative of autonomic activities; and a stimulationcontrol circuit coupled to the stimulation output circuit and theautonomic balance monitoring circuit, the stimulation control circuitincluding: a sympathetic stimulation controller adapted to adjust thesympathetic stimulation frequency to control whether the delivery of thesympathetic stimulation pulses results in excitation or inhibition ofthe sympathetic nerve; and a parasympathetic stimulation controlleradapted to adjust the parasympathetic stimulation frequency to controlwhether the delivery of the parasympathetic stimulation pulses resultsin excitation or inhibition of the parasympathetic nerve.
 2. The systemof claim 1, wherein the stimulation control circuit comprises astimulation parameter adjustment circuit adapted to adjust a pluralityof stimulation parameters controlling the delivery of the sympatheticstimulation pulses and parasympathetic stimulation pulses based on theone or more signals indicative of autonomic activities.
 3. The system ofclaim 2, wherein the stimulation parameter adjustment circuit isprogrammable and is adapted to adjust the plurality of stimulationparameters using programmable parameters mapping the one or more signalsindicative of autonomic activities to the stimulation parameters.
 4. Thesystem of claim 2, wherein the stimulation parameter adjustment circuitcomprises: a sympathetic stimulation parameter adjustment module adaptedto adjust one or more sympathetic stimulation parameters of theplurality of stimulation parameters; and a parasympathetic stimulationparameter adjustment module adapted to adjust one or moreparasympathetic stimulation parameters of the plurality of stimulationparameters, wherein the sympathetic stimulation controller is adapted tocontrol the delivery of the sympathetic stimulation pulses using the oneor more sympathetic stimulation parameters, and the parasympatheticstimulation controller is adapted to control the delivery of theparasympathetic stimulation pulses using the one or more parasympatheticstimulation parameters.
 5. The system of claim 4, wherein thestimulation parameter adjustment circuit is adapted to adjust theplurality of stimulation parameters dynamically using feedback controlwith one or more inputs including the one or more signals indicative ofautonomic activities.
 6. The system of claim 4, wherein the stimulationparameter adjustment circuit is adapted to further adjust the pluralityof stimulation parameters based on a predetermined time schedule.
 7. Thesystem of claim 4, wherein the autonomic balance monitoring circuitcomprises a nerve traffic sensing circuit adapted to sense one or moreneural signals indicative of the autonomic activities, and thestimulation parameter adjustment circuit is adapted to adjust theplurality of stimulation parameters based on the one or more neuralsignals.
 8. The system of claim 7, wherein the nerve traffic sensingcircuit comprises: a sympathetic traffic sensing circuit adapted tosense at least one sympathetic neural signal indicative of sympatheticnerve traffic; and a parasympathetic traffic sensing circuit adapted tosense at least one parasympathetic neural signal indicative ofparasympathetic nerve traffic.
 9. The system of claim 4, wherein theautonomic balance monitoring circuit comprises a surrogate signalsensing circuit adapted to sense one or more surrogate signalsindicative of the autonomic activities, and the stimulation parameteradjustment circuit adapted to adjust the plurality of stimulationparameters based on the one or more surrogate signals.
 10. The system ofclaim 9, wherein the surrogate signal sensing circuit comprises a heartrate variability (HRV) sensing circuit to sense an HRV and produce asurrogate signal of the one or more surrogate signals based on thesensed HRV.
 11. The system of claim 4, wherein the autonomic balancemonitoring circuit comprises a physiological function sensing circuit tosense one or more physiological function signals each indicative of oneof more physiological functions related to the autonomic activities, andthe stimulation parameter adjustment circuit is adapted to adjust theplurality of stimulation parameters based on the one or morephysiological function signals.
 12. The system of claim 11, wherein thephysiological function sensing circuit comprises a heart sound sensingcircuit to sense a signal indicative of heart sounds.
 13. The system ofclaim 11, wherein the autonomic balance monitoring circuit comprises anerve traffic sensing circuit adapted to sense one or more neuralsignals indicative of the autonomic activities and the physiologicalfunction sensing circuit, and the stimulation parameter adjustmentcircuit is adapted to adjust the plurality of stimulation parametersbased on the one or more neural signals and the one or morephysiological function signals.
 14. The system of claim 11, wherein theautonomic balance monitoring circuit comprises a surrogate signalsensing circuit adapted to sense one or more surrogate signalsindicative of the autonomic activities and the physiological functionsensing circuit, and the stimulation parameter adjustment circuit isadapted to adjust the plurality of stimulation parameters based on theone or more surrogate signals and the one or more physiological functionsignals.
 15. The system of claim 1, further comprising an implantablehousing to house the stimulation output circuit, the autonomic balancemonitoring circuit, and the stimulation control circuit.
 16. The systemof claim 15, further comprising one or more implantable neural leadscoupled to the stimulation output circuit, the one or more neural leadsconfigured for delivering the sympathetic stimulation pulses andparasympathetic stimulation pulses.
 17. The system of claim 15, furthercomprising a cardiac stimulation circuit coupled to the stimulationcontrol circuit and housed within the implantable housing, the cardiacstimulation circuit adapted to deliver cardiac stimulation pulses incoordination with the delivery of the sympathetic stimulation pulses andparasympathetic stimulation pulses.
 18. The system of claim 17, whereinthe cardiac stimulation circuit comprises a cardiac resynchronizationtherapy device.
 19. The system of claim 17, wherein the cardiacstimulation circuit comprises a cardiac remodeling control therapydevice.
 20. The system of claim 15, further comprising an externalsystem including: an external device communicatively coupled to thestimulation control circuit via telemetry; a remote device; and atelecommunication network coupled between the external device and theremote device.
 21. The system of claim 1, wherein the stimulationcontrol circuit is configured to control simultaneous delivery of thesympathetic stimulation pulses to result in the inhibition of thesympathetic nerve and parasympathetic stimulation pulses to result inthe excitation of the parasympathetic nerve.